Dengue is the most significant arthropod-transmitted viral infection of humans. Both in the context of natural infection and vaccination, human antibodies are necessary for clearing dengue virus (DENV). Paradoxically, under some conditions antibodies can also enhance the ability of DENV to infect cells and antibodies have been demonstrated to exacerbate disease in animal models of dengue. Despite the evidence that antibodies are important in dengue pathogenesis, very little is known about the binding and functional properties of the human antibody response to DENV. This is a remarkable gap in our knowledge given the scale of the global dengue problem. Based on preliminary studies from our group, here we propose to test the hypothesis that new epitopes created by the assembly and close packing of viral proteins on the surface of the virus are the main targets of the functionall important human antibody response. The impact of this work will be far ranging as it will redirect a field that has mainly focused on B-cell epitopes on subunits of E protein to consider new structural features and epitopes created following viral assembly. Our studies are divided into the following aims. In aim 1 we will define the main antigens and epitopes recognized by neutralizing antibodies in human immune serum. In aim 2 we will test the hypothesis that DENV enhancing antibodies in human immune serum mainly target the viral pre-membrane protein. The significance of the work is high because the studies are directly relevant to developing new vaccines and for evaluating current vaccines entering clinical trials.